Transformation leading to neoplasia of "target" cells from different species, including human, is being studied with the ultimate aim of understanding critical steps leading to transformation of human cells. There are differences in control mechanisms between rodent species that are readily and reproducibly transformable and human cells that are relatively refractory to transformation. Carcinogen treatment of cells from normal or individuals with genetic disorders only results in "transitory" transformation. Therefore, to induce immortality in human cells proto-oncogenes are being introduced into cells to facilitate the expression of malignancy when combined with pre- or post-carcinogen exposure. The quantitative Syrian hamster embryo cell (HEC) transformation model is being used to study some of the underlying biology of transformation. A lymphokine, leukoregulin (LR), inhibits promoted transformation. Results of pulse experiments prove that it causes a transient physiological alteration of normal cells making them refractory to carcinogen-induced transformation. Dose-dependent transformation of HEC occurs with the non-mutagen, bisulfite, a chemical ineffective in inducing DNA damage or chromosome aberrations. Permanent, tumorigenic lines with a variety of chromosome changes, including increased ploidy and chromosome markers, were obtained. Regardless of the chromosome changes, all neoplastic cell lines have identical protein changes (new, missing, and shifted proteins). Comparison of 0-6 methylguanine lesions and methylating carcinogen-induced HEC transformation suggests that the target for initiation is 50-500 genes, a number inconsistent with the concept of a single base mutation. Tumorigenic HEC contain activated oncogenes not related to ras. In the guinea pig transformation model a ras-related proto-oncogene becomes activated concurrently with tumorigenicity many months after carcinogen treatment. An 11KB EcoR1 DNA fragment related to ras has been cloned from 3T3 cells transformed by DNA from a guinea pig cloned line.